6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one derivatives as protein kinase modulators

Abstract

There are provided 3,5-disubstituted derivatives of 6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one compounds of formula (I) or a pharmaceutically acceptable salt thereof as defined in the present specification, which modulate the activity of protein kinases. The compounds are therefore useful in treating diseases caused by dysregulated protein kinase activity. In particular, such diseases to be treated with a compound of formula (I) of the present invention is one caused by and/or associated with disregulated protein kinase activity selected from the group consisting of cancer, viral infection, prevention of AIDS development in HIV-infected individuals, cell proliferative disorders, autoimmune and neurodegenerative disorders. The present invention also relates to processes for preparing the compounds of formula (I), combinatorial libraries thereof, pharmaceutical compositions comprising them, and methods of treating diseases utilizing pharmaceutical compositions comprising a compound of formula (I).

The invention claimed is: 
     
       1. A compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —NR 3 R 4  or —OR 3 ; 
         R 2  is a hydrogen atom or an optionally substituted group selected from straight or branched C 1 -C 6  alkyl, aryl, heteroaryl, aryl C 1 -C 6  alkyl and heteroaryl C 1 -C 6  alkyl; 
         R 3  and R 4 , the same or different, are each independently hydrogen atom or an optionally substituted group selected from straight or branched C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, cycloalkyl C 1 -C 6  alkyl, heterocyclyl, heterocyclyl C 1 -C 6  alkyl, aryl, aryl C 1 -C 6  alkyl, heteroaryl and heteroaryl C 1 -C 6  alkyl, or R 3  and R 4 , taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 3 to 7 membered heterocyclyl or heteroaryl ring, optionally containing one additional heteroatom or heteroatomic group selected from S, O, N and NH; or a pharmaceutically acceptable salt thereof, wherein the optionally substituted group of R 2 , R 3  and R 4  is substituted in any of its free positions by 1 to 6 groups, selected from the groups consisting of: halogen, nitro, oxo groups (═O), carboxy, cyano, C 1 -C 6  alkyl, polyfluorinated alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl, heteroaryl; amino groups and derivatives thereof; carbonylamino groups and derivatives thereof; hydroxy groups and derivatives thereof; carbonyl groups and derivatives thereof; and sulfurated derivatives, wherein when R 1  is —NR 3 R 4 , only one of R 3  and R 4  are hydrogen and when R 1  is —OR 3 , R 3  is not hydrogen. 
       
     
     
       2. A compound of formula (I) according to  claim 1  wherein R 1  is —NH 2  or NHR 3  and R 3  is a straight or branched C 1 -C 6  alkyl or C 2 -C 6  alkenyl group or it is an optionally substituted aryl or arylalkyl group, wherein the optionally substituted aryl or arlyalkyl of R 3  is substituted in any of its free positions by 1 to 6 groups, selected from the groups consisting of: halogen, nitro, oxo groups (═O), carboxy, cyano, C 1 -C 6  alkyl, polyfluorinated alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl, heteroaryl; amino groups and derivatives thereof; carbonylamino groups and derivatives thereof; hydroxy groups and derivatives thereof; carbonyl groups and derivatives thereof; and sulfurated derivatives. 
     
     
       3. A compound of formula (I) according to  claim 1  wherein R 2  is hydrogen or an optionally substituted aryl or heteroaryl group, wherein the optionally substituted aryl or heteroaryl of R 2  is substituted in any of its free positions by 1 to 6 groups, selected from the groups consisting of: halogen, nitro, oxo groups (═O), carboxy, cyano, C 1 -C 6  alkyl, polyfluorinated alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, heterocyclyl, aryl, heteroaryl; amino groups and derivatives thereof; carbonylamino groups and derivatives thereof; hydroxy groups and derivatives thereof; carbonyl groups and derivatives thereof; and sulfurated derivatives. 
     
     
       4. A compound of formula (I) according to  claim 1  wherein R 2  is a fragment denoted by any of codes A1-A18 and R1 is a fragment denoted by any of codes B1-B32: 
       
         
           
                 
                 
                 
                 
               
                     
                 
                   Fragment 
                   CODE 
                   Fragment 
                   CODE 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A9 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A10 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A11 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A12 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A13 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A14 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A7 
                   H—M 
                   A15 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A8 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A16 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A17 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   A18 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B1 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B8 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B2 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B9 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B10 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B11 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B5 
                   HO—M 
                   B12 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B6 
                   H 2 N—M 
                   B13 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B14 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B15 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B24 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B25 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B17 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B26 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B18 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B27 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B19 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B28 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B20 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B29 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B21 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B30 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B22 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B31 
                 
                     
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B23 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   B32. 
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       5. A process for preparing a compound of the formula (I) or the pharmaceutically acceptable salts thereof, as defined in  claim 1 , which process comprises:
 a) decarboxylating a compound of formula (II): 
 
       
         
           
           
               
               
           
         
         b) reacting the resultant compound of formula (III): 
       
       
         
           
           
               
               
           
         
         with a compound of formula (IV) or a salt thereof: 
       
       
         
           
           
               
               
           
         
         wherein R 3  is a C 1 -C 6  alkyl group, so as to obtain a compound of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein R 3  is a C 1 -C 6  alkyl group and R 2  is hydrogen, or a pharmaceutically acceptable salt thereof and, if necessary or desired, performing one or more of the following additional steps:
 separating the compound of formula (I) into the single isomers; 
 converting a compound of formula (I) into a different compound of formula (I) by introduction on the imidazole moiety of a R 2  group as defined in  claim 1  but different from hydrogen; 
 converting a compound of formula (I) into a different compound of formula (I) by replacing the group —OR 3  with a different group R 1  as defined in  claim 1 ; 
 converting a compound of formula (I) into a pharmaceutically acceptable salt or converting a salt into the free compound (I). 
 
       
     
     
       6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as defined in  claim 1 , and at least one pharmaceutically acceptable carrier and/or diluent. 
     
     
       7. A pharmaceutical composition according to  claim 6  further comprising one or more chemotherapeutic agents. 
     
     
       8. A product comprising a compound of formula (I) as defined in  claim 1  or a pharmaceutical composition thereof comprising said compound and at least one pharmaceutically acceptable carrier and/or diluent, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.